The clinical use of platinum complexes such as cisplatin and carboplatin in cancer chemotherapy is well established in the art. A number of platinum complexes, such as PLATINOL.RTM., a registered trademark of cisplatin manufactured by Bristol Myers, Co., are used to treat testicular, ovarian, head and neck, and small-cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumor becoming refractory to treatment by the agent.
To overcome the nephrotoxic effects of cisplatin, a second-generation analog, carboplatin, was developed. PARAPLATIN.RTM. is a registered trademark for carboplatin manufactured by Bristol-Myers, Co. Carboplatin, or [Pt(NH.sub.3).sub.2 (CBDCA)] (where CBDCA is 1,1'cyclobutane dicarboxylate), is effective against the same spectrum of carcinomas as cisplatin, but exhibits a marked reduction in the nephrotoxic effects.
A number of different platinum compounds have been developed in an attempt to treat different tumors or carcinomas. For instance, U.S. Pat. No. 4,225,529 discloses the use of a cis coordination compound of platinum having four ligands which are selected from the group consisting of halides, sulphates, phosphates, nitrates, carboxylates, and same or different straight-chain amines which are coordinated to the platinum atom through their nitrogen atoms. These complexes are utilized for treating L-1210 leukemia in mice.
Also, U.S. Pat. Nos. 4,250,189, 4,553,502, and 4,565,884 relate to various Pt(II) and Pt(IV) complexes having anti tumor activity. These bis(platinum) complexes are linked with a carboxylate linkage such that upon administration of these complexes to the patient, the complexes undergo rapid hydrolysis to produce two cis monoplatinum moieties which are then delivered to the active site. 3
Additionally, U.S. Pat. No. 4,797,393, discloses a bis(platinum) complex which complex is delivered intact to the active site. This bis(platinum) complex has a bridging diamine or polyamine ligand and has primary or secondary amines or pyridine type nitrogens attached to the platinum complex, as well as two different or identical ligands which may be a halide, sulphate, phosphate, nitrate, carboxylate, substituted carboxylate or dicarboxylate. Also, commonly assigned application Ser. No. 07/713,105 relates to bis(platinum) complexes wherein the platinum moieties are linked by a diamine bridging agent, and wherein the platinum moieties are attached to ionic and neutral groups such that the net charge on the two platinum coordination spheres is 2+ or 1+.
However, critical problems still exist which limit the effective use of platinum complexes as therapeutics, most especially their narrow spectrum of activity against different tumors and the development of tumor cells which are resistant to the cytotoxic effects of cisplatin. (Loehrer et al., Ann, Intern. Meal., (1984), 100, 704-711). For a general review relating to available platinum analogs, see, Christian, Michael, Seminars in Oncology, 1992, 19, 720-733.
It is generally believed that platinum complexes such as cisplatin manifest their biological activity through covalent interaction with DNA. In particular, cisplatin induces the formation of a range of adducts on DNA including monodentate adducts, bidentate adducts, such as GG or AG, and GNG intrastrand crosslinks. (Reedijk et al., Structure and Bonding, (1987), 67, 53-89). To a lesser extent, cisplatin also results in interstrand GG crosslinks and DNA-protein crosslinks. (Rahmouni et at., Biochemistry, (1987), 26, 7229-7234). These DNA lesions result in conformational changes which are reflected in bending and local unwinding of the DNA. These DNA lesions have been reported to inhibit the activity of various DNA polymerase. (Vallan et al., Nucl. Acids Res., (1988), 16, 4407-4418; Pinto et al., Proc. Natl. Acad. Sci, (1985), 82, 4616-4619; and Gralla et at., Cancer Res., (1987), 47, 5092-5096). The interstrand crosslink between two neighboring guanine bases has also been shown to inhibit RNA polymerase function. (Lemaire et al., Proc. Natl. Acad. Sci., (1991), 88, 1982-1985). Accordingly, the cytotoxic effects of cisplatin are most likely attributable to the combined effects of these separate DNA lesions, rather than the result of any one specific lesion event.
Mono(platinum) and bis(platinum) complexes respectively containing one or two platinum atoms are known in the art. (See, e.g., U.S. Pat. Nos. 4,225,529, 4,250,189, 4,533,502, 4,565,884, 4,571,335 and 4,797,393). For example, mono(platinum) complexes include monomeric chloramine square-planar Pt(II) compounds which are four coordinate. The relative number of chloride and ammonia groups in such compounds may vary and these compounds may therefore be described by the general formula: EQU [PtCl.sub.m (NH.sub.3).sub.4-m ].sup.(2-m)+
Thus, the structure of these compounds may vary from [Pt(NH.sub.3).sub.4 ].sup.2+ where m=0 to PtCl.sub.4.sup.2- where m=4. Since Cl is more substitution labile in comparison to ammonia, the complexes [PtCl.sub.2 (NH.sub.3).sub.2 ] and [PtCl(NH.sub.3).sub.3 ]Cl are considered bifunctional and monofunctional respectively, wherein the bi and mono prefixes refers to the number of leaving ligands. The charge of the complex is obtained by considering that the Pt(II) cation has a formal charge of +2 and thus requires a negative charge of -2 for charge neutralization. For example, when m=0, neutralization is provided by the presence of two chloride anions.
Coordinate bond formation results in electron pairing in the Pt--Cl bond. However, since the ammonia ligand is considered to be neutral, the bonding may be described as electron-pair donation from NH.sub.3 to the empty orbitals on the Pt(II) atom. Thus, no electron sharing between the Pt and NH.sub.3 group takes place. Because of this absence of electron sharing, the number of neutral ligands does not affect the overall charge in the Pt coordination sphere. Thus, [Pt(NH.sub.3).sub.4 ].sup.2+ is formally a 2+ cation requiring non-coordinating anion or anions, or counter-anions, having a net negative charge of 2- for neutralization of the complex. For example, neutralization can be provided by two mononegatively charged anions (e.g., NO.sub.3.sup.-, Cl.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.-, and monocarboxylates having the general formula RCOO.sup.-) or a single dinegatively charged anion (e.g., SO.sub.4.sup.2-, dicarboxylates having the general formula (RCOO).sub.2.sup.2-). Therefore, by the same principles, [PtCl.sub.2 (NH.sub.3).sub.2 ] is a neutral complex. Moreover, in some cases, Pt(II) anions may serve as counter-anions. An example is the well known Magnus salt [Pt(NH.sub.3 ).sub.4 ].sup.2+ [PtCl.sub.4 ].sup.2-.
It is noted that artionic ligands such as Cl- may be either coordinately bound (i.e., forming a Pt--Cl bond) or may act as a counter-anion without any need for covalent bond formation. The exact form that anions such as Cl- are comprised in a given platinum complex depends both on theoretical considerations (kinetic vs. thermodynamic effects) and the actual synthetic procedures utilized to make the complex (e.g., the extent of reaction, acidity, concentration of the particular anion, such as the concentration Cl- which is contained in the reaction mixture). These considerations are applicable to other anionic and neutral ligands as well.
Examples of neutral ligands typically comprised in monoplatinum complexes include, e.g., olefins such as ethylene (C.sub.2 H.sub.4), propene and 2-butene; phosphines (PR.sub.3), sulfides (SR.sub.2), sulfoxides (R.sub.2 SO), ammonia (NH.sub.3), primary amines (RNH.sub.2) and heterocyclic amines such as pyridine or quinoline. Examples of typical anionic ligands contained in platinum complexes include halides (e.g., Cl.sup.-, Br.sup.-, I.sup.-) and pseudohalides such as SCN.sup.-, CN.sup.-, and NO.sub.3.sup.-. The term "pseudohalide" comprises the definition found on page 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson). Alternative suitable pseudohalides may be found in many standard inorganic chemistry books. e.g., such as Inorganic Chemistry by Cotton and Wilkinson.
The fact that the overall charge of monoplatinum complexes depends on the relative number of neutral and anionic ligands which are bound to the Pt(II) metal, e.g., NH.sub.3 and Cl.sup.- ligands, is equally applicable for polynuclear complexes (which contain more than one Pt(II) coordinate spheres), and for Pt(IV) containing complexes wherein the oxidation state of the platinum moiety is 4+. For example, dinuclear complexes where two equivalent Pt(II) coordination spheres are linked by a diamine bridging agent may be represented by the general formula [{PtCl.sub.m (NH.sub.3).sub.3-m }.sub.2 (diamine)].sup.2(2-m)+. Thus, when m=2, and two bifunctional coordination spheres are present, the compound is neutral. In contrast, when m=1, only monofunctional coordination spheres are present and the Pt moiety has a formal charge of 2+ which must be counterbalanced by one or more counter-anions having a net charge of 2-.